Composition that is self-foaming in an acid medium, and method for preparing same

Abstract

A composition that is self-foaming in an acid medium, and includes: at least one hydrophilic polymer, at least one compound capable of crosslinking the hydrophilic polymer by forming ionic bonds, at least one foaming agent, and at least one foam stabilizer agent; and to the use thereof as a drug, particularly for preventing and/or treating obesity.

Claims

1. A composition comprising: at least one hydrophilic polymer selected from alginates, from 0.01 to 50 wt % of at least one compound (a) selected from the group consisting of carbonates of divalent metal cations, carbonates of trivalent metal cations, hydroxyapatite Ca.sub.10(PO.sub.4).sub.6OH.sub.2 and mixtures thereof, from 0.01 to 50 wt % of at least one compound (b) selected from carbonates and bicarbonates of monovalent alkali metal cations, and at least one foam stabilizer, wherein a ratio of the quantity of divalent and/or trivalent metal cations in the compound (a) to the quantity of monovalent alkali metal cations in the compound (b) is greater than or equal to 0.05, the quantities of cations being expressed in moles.

2. The composition as claimed in claim 1, wherein the content by weight of hydrophilic polymer is from 10% to 99.5%, the contents being expressed in weight of dry matter of the composition.

3. The composition as claimed in claim 1, wherein the compound (a) is selected from carbonates of divalent metal cations.

4. The composition as claimed in claim 3, wherein the compound (a) is chosen from the group consisting of calcium carbonate CaCO.sub.3, manganese carbonate MnCO.sub.3, silver carbonate AgCO.sub.3, iron carbonate FeCO.sub.3, copper carbonate CuCO.sub.3, magnesium carbonate MgCO.sub.3, and mixtures thereof.

5. The composition as claimed in claim 4, wherein the compound (a) is calcium carbonate CaCO.sub.3.

6. The composition as claimed in claim 1, wherein the foam stabilizer is selected from the group consisting of structure-forming agents, surfactants and mixtures thereof.

7. The composition as claimed in claim 1, wherein the compound (b) is selected from the group consisting of sodium carbonate Na.sub.2CO.sub.3, sodium bicarbonate NaHCO.sub.3, potassium bicarbonate KHCO.sub.3, and mixtures thereof.

8. The composition as claimed in claim 1, which is a hydrogel.

9. The composition as claimed in claim 1, which is in dry form.

10. The composition as claimed in claim 9, which is a xerogel, an aerogel or a cryogel.

11. The composition as claimed in claim 1, which is the core of a capsule with a core/shell structure and wherein said core is covered over all or part of its surface with at least one coating layer.

12. The composition as claimed in claim 1, which is part of a dietary kit further comprising, in a separate part of one and the same packaging, at least a portion of foodstuffs.

13. The composition as claimed in claim 1, for the preparation of a food composition for animals in the form of pellets, snacks or biscuits, said food composition further comprising a portion of food.

14. A composition as claimed in claim 1, packaged in the body of a syringe for oral administration.

15. A method of manufacturing a composition as claimed in claim 1, comprising introducing the following into an aqueous medium: the hydrophilic polymer, the compound (b), the compound (a), and the foam stabilizer.

Description

FIGURES

(1) FIG. 1a: graphical representation of the change in the degree of swelling of different compositions (ordinate) as a function of time in minutes (abscissa).

(2) Curve 1 shows the variation of the degree of swelling of a composition according to the invention in which the foam stabilizer is Tween 80® (composition 1).

(3) Curve 2 shows the variation of the degree of swelling of a composition according to the invention in which the foam stabilizer is gelatin (composition 2).

(4) Curve 3 shows the variation of the degree of swelling of a composition free from foam stabilizer (composition 3).

(5) Curves 4 and 5 are merged and show the variation of the degree of swelling of two compositions free from foaming agent (compositions 4 and 5 respectively).

(6) Curve 6 shows the variation of the degree of swelling of a hydrogel composition as described in the prior art (composition 8).

(7) FIG. 1b: is an enlarged detail of FIG. 1a corresponding to the time interval [0, 15 minutes].

(8) FIG. 2: graphical representation of the variation over time (abscissa) of the occupied volume of the stomach (ordinate) while eating a meal after ingesting a hydrogel composition of the prior art at t=0, the occupied volume of the stomach being expressed as a percentage of the total volume of the stomach.

(9) Curve 1 shows the total occupied volume of the stomach (foodstuffs and liquid), the patient experiencing a sensation of satiety when this curve reaches 100%.

(10) Curve 2 shows the volume of foodstuffs ingested by the patient.

(11) Curve 3 shows the volume of foodstuffs present in the stomach.

(12) Curve 4 shows the volume occupied by the ingested hydrogel.

(13) Curve 5 shows the volume of liquid present in the stomach.

(14) FIG. 3: graphical representation of the variation over time (abscissa) of the occupied volume of the stomach (ordinate) while eating a meal after ingesting a composition according to the invention at t=0, the occupied volume of the stomach being expressed as a percentage of the total volume of the stomach.

(15) Curve 1 shows the total occupied volume of the stomach (foodstuffs and liquid), the patient experiencing a sensation of satiety when this curve reaches 100%.

(16) Curve 2 (dashed line) shows the volume of foodstuffs ingested by the patient.

(17) Curve 3 (solid line) shows the volume of foodstuffs present in the stomach.

(18) Curve 4 shows the volume occupied by the ingested composition according to the invention.

(19) Curve 5 shows the volume of liquid present in the stomach.

(20) The invention is illustrated by the following nonlimiting examples.

EXPERIMENTAL SECTION

(21) In these examples, the parts and percentages are expressed by weight unless stated otherwise.

(22) Equipment and Reagents

(23) Equipment: beaker, mechanical stirrer with anchor blade, heating plate, syringe and needle.

(24) Reagents: water-soluble sodium alginate polymer (CAS: 9005-38-3), commercially available from Sigma Aldrich under reference A2033. calcium carbonate CaCO.sub.3 (CAS: 471-34-1), commercially available from Sigma Aldrich under reference 398101. sodium bicarbonate NaHCO.sub.3 (CAS: 144-55-8), commercially available from Sigma Aldrich under reference S5761. TWEEN 80® (CAS: 9005-65-6), commercially available from Sigma Aldrich under reference P1754. food gelatin derived from pigs in the form of plates commercially available from the company McCormick France SAS. citric acid (CAS: 77-92-9) in the form of an aqueous solution at 2.6%.
Protocol for Measuring the Variation of the Degree of Swelling of a Composition Over Time

(25) 2 mL of a composition according to the invention is put in a class A measuring cylinder graduated from 0 to 100 mL. 50 mL of an aqueous solution whose pH has been fixed at 2 by adding citric acid is then introduced carefully into the graduated measuring cylinder. It is important to introduce the aqueous solution into the graduated measuring cylinder carefully so as to be able to monitor the variation of the volume of the system.

(26) The volume of the composition is recorded at regular intervals using a chronometer, between 10 s and 1 min depending on the measurement conditions.

(27) The swelling of the composition is monitored until the volume stabilizes and reaches a plateau. The volume corresponding to this plateau is considered to be the volume corresponding to the maximum swelling of the composition in the conditions investigated. The degree of swelling of the composition is determined from the following equation:
G=(Vt−Vi)/Vi

(28) with:

(29) G: degree of swelling (without units)

(30) Vt: volume determined at time t (in mL)

(31) Vi: initial volume of the composition after drying (in mL)

(32) The initial volume of the composition after drying Vi is determined as follows: 2 mL of the initial composition is poured into an aluminum dish with a diameter of 2 cm and put in an oven at 70° C. for 12 h. The dry product is then in the form of a disk with a diameter of 2 cm, the thickness of which is measured using a micrometer caliper gauge. The volume of this disk represents the initial volume of the composition after drying.

(33) The measurements of swelling are repeated 3 times in order to determine an average degree of swelling.

Example 1: Preparation of the Compositions

(34) Composition 1 (According to the Invention):

(35) 1 g of sodium alginate was dissolved in 46.9 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(36) 1 g of calcium carbonate CaCO.sub.3 and 1 g of sodium bicarbonate NaHCO.sub.3 were dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(37) Finally, 100 mg of a mixture of surfactants (TWEEN 80®) was added to the dispersion.

(38) Composition 2 (According to the Invention):

(39) 1 g of sodium alginate was dissolved in 46.9 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(40) 1 g of calcium carbonate CaCO.sub.3 and 1 g of sodium bicarbonate NaHCO.sub.3 were dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(41) Finally, 100 mg of a structure-forming agent (gelatin) was added to the dispersion.

(42) Composition 3 (Comparative, without Foam Stabilizer):

(43) 1 g of sodium alginate was dissolved in 47 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(44) 1 g of calcium carbonate CaCO.sub.3 and 1 g of sodium bicarbonate NaHCO.sub.3 were dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(45) Composition 4 (Comparative, without Foaming Agent):

(46) 1 g of sodium alginate was dissolved in 47.9 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(47) 1 g of calcium carbonate CaCO.sub.3 was dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(48) Finally, 100 mg of a mixture of surfactants (TWEEN 80®) was added to the dispersion.

(49) Composition 5 (Comparative, without Foaming Agent):

(50) 1 g of sodium alginate was dissolved in 47.9 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(51) 1 g of calcium carbonate CaCO.sub.3 was dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(52) Finally, 100 mg of a structure-forming agent (gelatin) was added to the dispersion.

(53) Composition 6 (Comparative, without Compound Capable of Crosslinking the Hydrophilic Polymer by Forming Ionic Bonds):

(54) 1 g of sodium alginate was dissolved in 47.9 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(55) 1 g of sodium bicarbonate NaHCO.sub.3 was dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(56) Finally, 100 mg of a mixture of surfactants (TWEEN 80®) was added to the dispersion.

(57) Composition 7 (Comparative, without Compound Capable of Crosslinking the Hydrophilic Polymer by Forming Ionic Bonds):

(58) 1 g of sodium alginate was dissolved in 47.9 mL of deionized water (concentration fixed at 20 g/L-2 wt % of alginate) with stirring with a motor and an anchor blade until a homogeneous solution was obtained (without aggregates of undissolved sodium alginate).

(59) 1 g of sodium bicarbonate NaHCO.sub.3 was dispersed in the sodium alginate stock solution, stirring with an anchor blade until a homogeneous dispersion was obtained.

(60) Finally, 100 mg of a structure-forming agent (gelatin) was added to the dispersion.

(61) Composition 8 (Comparative, According to the Prior Art):

(62) Composition 8 corresponds to a composition of the hydrogel type obtained from polyacrylamide.

(63) It corresponds to the composition studied in the scientific article T. BERTRAND et al., Dynamics of Swelling and Drying in a Spherical Gel, PHYS. REV. APPLIED, Vol. 6, 2016.

Example 2: Comparison of the Variation of the Degree of Swelling as a Function of Time of Compositions According to the Invention Relative to a Composition of the Prior Art

(64) The variation of the degree of swelling of the compositions according to the invention 1 and 2 was determined according to the measurement protocol described above.

(65) The results obtained are shown in FIGS. 1a and 1b, where curves 1 and 2 correspond respectively to the results obtained for composition 1 and for composition 2, according to the invention.

(66) The degree of swelling of composition 8 of the hydrogel type according to the prior art was evaluated from the experimental data presented in the article T. BERTRAND et al., Dynamics of Swelling and Drying in a Spherical Gel, PHYS. REV. APPLIED, Vol. 6, 2016.

(67) The variation over time of the radius of beads of hydrogel corresponding to composition 8 is presented in FIG. 1a) of that article.

(68) By regarding these beads of hydrogel as spheres, it is possible, starting from their radius r, to calculate their volume at each instant by applying the following formula (1):
V=4/3πr.sup.3  (1)

(69) From the volume occupied at each instant, it is possible to deduce the degree of swelling of the hydrogel at each instant by subtracting from it the volume occupied initially by the composition and then dividing the result for the difference by the initial volume occupied by the composition.

(70) The results obtained are shown in FIGS. 1a and 1b, curve 6.

(71) Referring to FIGS. 1a and 1b, curve 1 shows the variation of the degree of swelling of composition 1 according to the invention, curve 2 shows the variation of the degree of swelling of composition 2 according to the invention, and curve 6 shows the variation of the degree of swelling of composition 8, according to the prior art.

(72) The maximum swelling observed for composition 8, according to the prior art, is reached in 240 minutes and corresponds to a degree of swelling of 261.

(73) The maximum degree of swelling observed for composition 1 according to the invention is reached in 4 minutes in contact with the acid medium and corresponds to a degree of swelling of 318.

(74) The maximum swelling observed for composition 2 according to the invention is reached in 2 minutes in contact with the acid medium and corresponds to a degree of swelling of 381.

(75) Thus, compositions 1 and 2, according to the invention, have a degree of swelling greater than that of composition 8, according to the prior art. Moreover, this greater swelling is reached in a much shorter time: between 2 and 4 minutes for a composition according to the invention and about 4 hours for a composition according to the prior art.

(76) In conclusion, the kinetics of swelling of compositions 1 and 3, according to the invention, is much quicker than that of composition 8, according to the prior art. Compositions 1 and 2, according to the invention, are therefore able to give the patient a sensation of satiety much more quickly than the hydrogel composition of the prior art.

Example 3: Simulation of the Volume Distribution of the Stomach Contents when Eating a Meal after Ingesting a Composition According to the Invention or a Composition According to the Prior Art

(77) The results obtained in example 2 were used for simulating the volume distribution of the stomach contents when eating a meal and after ingestion firstly of a composition of the hydrogel type according to the prior art (composition 8), and secondly of a composition according to the invention (composition 1). The results obtained are presented in FIGS. 2 and 3.

(78) The time for eating a meal is on average 30 minutes. The model proposed is based on ingestion of hydrogel at the start of a meal, and then ingestion of foodstuffs until satiety is attained, evaluation taking place over a time of 30 minutes.

(79) Composition 8:

(80) Referring to FIG. 2:

(81) Curve 1 shows the total occupied volume of the stomach.

(82) Curve 2 shows the volume of foodstuffs ingested by the patient.

(83) Curve 3 shows the volume of foodstuffs present in the stomach.

(84) Curve 4 shows the volume of the stomach occupied by the hydrogel, according to the

(85) prior art.

(86) Curve 5 shows the volume of liquid present in the stomach.

(87) The patient experiences a sensation of satiety when the whole volume of the stomach is occupied, or when curve 1 reaches 100%.

(88) A patient who has ingested a hydrogel according to the prior art therefore experiences a sensation of satiety 25 minutes after starting the meal.

(89) At this precise moment, the volume distribution of the stomach is as follows: 23% of the total volume of the stomach is occupied by the hydrogel (curve 4), and 77% of the total volume of the stomach is occupied by the foodstuffs ingested by the patient while eating the meal (curve 3).

(90) Since part of the food ingested has already passed into the intestine, the patient has in point of fact ingested a volume of foodstuffs equivalent to 80% of the total volume of the stomach (curve 2).

(91) It is also observed that the volume of liquid present in the stomach (curve 5) decreases starting from 15 minutes after taking the hydrogel and becomes almost zero starting from 20 minutes after ingestion of the hydrogel.

(92) This variation of the volume of liquid present in the stomach is evidence of the mechanism of swelling of the hydrogel according to the prior art: by absorption of water.

(93) Composition 1:

(94) Referring to FIG. 3:

(95) Curve 1 shows the total occupied volume of the stomach.

(96) Curve 2 (dashed line) shows the volume of foodstuffs ingested by the patient.

(97) Curve 3 (solid line) shows the volume of foodstuffs present in the patient's stomach.

(98) Curve 4 shows the volume occupied by the composition according to the invention.

(99) Curve 5 shows the volume of liquid present in the stomach.

(100) The patient experiences a sensation of satiety when the whole volume of the stomach is occupied, or when curve 1 reaches 100%.

(101) A patient who has ingested a hydrogel according to the prior art therefore experiences a sensation of satiety 14 minutes after starting the meal.

(102) At this precise moment, the volume distribution of the stomach is as follows: 38% of the total volume of the stomach is occupied by the composition according to the invention, and 46% of the total volume of the stomach is occupied by the foodstuffs ingested by the patient while eating the meal.

(103) Satiety is reached more quickly in this second case.

(104) As a result, the volume of food ingested by the patient and the volume of foodstuffs present in the stomach are almost equal: a very small amount of foodstuffs has had time to pass into the intestine.

(105) The remaining volume of the stomach is occupied by liquids (curve 5).

(106) It will also be noted that the volume of liquid present in the stomach does not decrease while eating the meal. Swelling of the composition according to the invention does not require absorption of liquid.

(107) In both cases, the compositions according to the invention and according to the prior art make it possible to reduce the volume of foodstuffs ingested by a patient in order to experience a sensation of satiety.

(108) Ingestion of a composition according to the invention gives a larger decrease of the volume of the foodstuffs ingested by the patient.

(109) In fact the sensation of satiety is experienced by the patient who has ingested a composition according to the invention after 14 minutes. The volume of foodstuffs ingested by the patient represents at this precise moment 47% of the total volume of the stomach.

(110) However, the sensation of satiety is experienced by the patient who has ingested a composition according to the prior art (composition 8) after 25 minutes. The volume of foodstuffs ingested by the patient represents at this precise moment 80% of the total volume of the stomach.

(111) The composition according to the invention therefore allows a sensation of satiety to be attained more quickly.

(112) Moreover, the composition according to the invention is a better “appetite suppressant”, in that its ingestion at the start of a meal allows a greater decrease in the volume of foodstuffs to be ingested by a patient in order to experience a sensation of satiety.

Example 4: Influence of the Acidity of the Medium on the Degree of Swelling of the Composition

(113) The swelling properties of different compositions according to the invention were evaluated at neutral pH (compositions 1 and 2) and at pH equal to 4 (composition 2 only).

(114) The protocol for measuring the degree of swelling of the compositions is similar to that described above, except that the aqueous composition is not at pH 2 but at pH 7 or 4.

(115) The results are presented below.

(116) Results:

(117) Swelling at Neutral pH (pH=7)

(118) In both cases, the compositions according to the invention (compositions 1 and 2) are simply diluted by the aqueous solution.

(119) The phenomena of release of gases and crosslinking do not occur. An expanded foam of sodium alginate is not obtained.

(120) Placed in a neutral medium, the composition according to the invention does not allow a hydrogel to be obtained in the form of an expanded foam.

(121) Swelling at pH Equal to 4

(122) No swelling is observed instantaneously after bringing composition 2 according to the invention into contact with the acid medium (pH=4).

(123) After 1 minute in contact with the acid medium, the composition according to the invention begins to swell.

(124) After 5 minutes, swelling of the composition has ended.

(125) The composition obtained has a low degree of swelling and the foam obtained is mechanically fragile.

(126) Placed in an acid medium at pH equal to 4, the composition according to the invention allows a hydrogel foam to be obtained.

(127) The degree of swelling of the composition is relatively low and the kinetics of swelling is slow.

Example 5: Influence of the Foam Stabilizer on the Degree of Swelling of the Composition

(128) The swelling properties of composition 3 (counter-example, free from foam stabilizer) were evaluated according to the protocol described above.

(129) The results obtained are shown in FIGS. 1a and 1b, curve 3.

(130) The maximum swelling observed for composition 3 is reached after 2 minutes in contact with the acid medium and corresponds to a degree of swelling of 126.

(131) Thus, compositions 1 and 2 according to the invention have a degree of swelling from 2.5 to 3 times greater than that of composition 4 that is free from foam stabilizer.

(132) The presence of a foam stabilizer in the compositions according to the invention therefore makes it possible to obtain a composition that is self-swelling in an acid medium and has a degree of swelling more than 2.5 times greater than that of a composition that is free from foam stabilizer.

Example 6: Influence of the Foaming Agent on the Degree of Swelling of the Composition

(133) The swelling properties of compositions 4 and 5 (counter-examples, free from foaming agent) were evaluated according to the protocol described above.

(134) The results obtained are shown in FIGS. 1a and 1b, curves 4 and 5.

(135) The results obtained for compositions 4 and 5 are very similar, curves 4 and 5 being merged.

(136) The maximum swelling observed for compositions 4 and 5 is reached after 5 minutes in contact with the acid medium and corresponds to a degree of swelling of 79%.

(137) Thus, compositions 1 and 2 according to the invention have a degree of swelling more than four times greater than that of compositions 4 and 5 free from foaming agent.

(138) The presence of a foaming agent in the compositions according to the invention therefore makes it possible to obtain a composition that is self-swelling in an acid medium and has a high degree of swelling, notably more than 4 times greater than that of a composition free from foaming agent.

Example 7: Influence of the Agent Capable of Crosslinking the Polymer by Forming Ionic Bonds on the Degree of Swelling of the Composition

(139) The swelling properties of compositions 6 and 7 (counter-examples, free from compound capable of crosslinking the hydrophilic polymer by forming ionic bonds) were evaluated according to the protocol described above.

(140) In both cases, the foaming agent is released by passage in an acid medium. We then observe formation of a foam that collapses quickly: the gas formed within the composition escapes from the hydrogel and does not allow a foam structure to be obtained.

(141) Compositions 6 and 7 are simply diluted by the aqueous solution.

(142) The presence of an agent capable of crosslinking the hydrophilic polymer by forming ionic bonds in the compositions allows a hydrogel to be obtained in the form of an expanded foam in an acid medium.